GB2166735A - Preparation of 3-hydroxy-3-methyl-glutaric acid - Google Patents

Abstract

3-Hydroxy-3-methyl-glutaric acid is prepared by direct oxidation with nitric acid of 3-methyl-1,3,5-pentanetriol.

Description

1 GB 2 166 735 A 1

SPECIFICATION

Process for the preparation of 3-hydroxy-3-methyl-giutaric acid The present invention relates to the preparation of 3-hydroxy-3-methyiglutaric acid, having the formula: 5 OH HOOC-Uh2-C-CH2-COOH 1 10 CH3 and more specifically to an improved process for such a preparation. The 3-hydroxy-3-methyl-glutaric acid (meglutol) is a compound present in the human organism and appears among the products of the endogenetic synthesis of cholesterol; it is endowed with hypolipidemic and hypocholesterolemic properties 15 which are well known in therapy and related to its properties of reducing, if administered at suitable dosages, the cholesterol synthesis.

This compound is prepared by synthesis according to several methods which can be grouped in few fundamental synthesis schemes.

A) Oxidation with ozone and hydrogen peroxide of dial lyl-methylca rbinol, which is in turn prepared bythe 20 use of the Grignard reactant, allyimagnesiumbromide (J.A.M. Chem. Soc., 76,1289,1954) followed by oxidation of this intermediate with alkali permanganates (Belgian Patent 872.650 of January 30, 1979).

B) Reaction according to Reformatsky between ethyl bromoacetate and ethyl acetoacetate (J.A.M. Chem.

Soc. 53,18433,1931; idem 75, 2377,1935), or reaction between alkali-metal derivatives of alkylacetates and acetylhalides (European Application No. 97.578 of January 4,1984), followed by saponification of the ethyl 25 diester.

C) Hydrolysis with alkali and hydrogen peroxide of giutaronitrile, which in turn can be obtained from 1-chloro-2,3-epoxy-2-methyl-propane and potassium cyanide (Synthesis 1981, 791).

To the above essential synthesis processes involving several steps, some of which are also difficular or dangerous for the industrial practicing, recently a new process has been added consisting in the permanganic oxidation of an intermediate, 3-m ethyl - 1,3,5-pe nta n etrio 1, this product being actually available on the market (European Patent Application No. 82344 of June 29, 1983).

This process, by which meglutol is directly prepared in one step only, is consequently potentially advantageous, mainly from the industrial point of view, with respect to the previous processes.

The advantages of this process have been confirmed by the laboratory experimental work, but its practicing in equipments of the industrial type raises problems and is not satisfactory as regards the results, mainly owing, to the big amount of inorganic salts which are present in the reaction product, whereby two types of problems exist: the particular physical appearance of the reaction residue which, owing to its glass consistency, can not be solubilized in the solvents used for the normal handling and equipments used in the industrial production; the presence in the raw reaction product of high amounts of inorganic salts which can 40 not be completely removed by crystallization without reducing also the final yield of meglutol, owing to its hydrophylic properties.

These drawbacks have been overcome with the new oxidation method of 3methyl-1,3,5-pentanetriol by which meglutol can be provided which is devoid of inorganic substances and consequently more adapted for the practicing in industrial plants.

The present invention thus relates to a synthesis process for the 3hydroxy-3-methyl-glutaric acid consisting in the oxidation with nitric acid, according to the following scheme 1, of 3-methyl1,3,5 pentanCtriol, an intermediate which is simple and readily practiceable in all its steps in the industrial plants and consequently characterized, with respect to the known processes, by the economicity and industrial feasibility.

Scheme 1 OH OH 1 1 HO -CH2-CH2- U-UH2-UH201-1 + nHN03 ---'-HOOC-CH2-C-UH2-UUUtl 1 Ut13 1 CH3 More particularly the present process is advantageously distinguished also with respect to the process disclosed in the European Application 82344 since the use of nitric acid in the oxidation of 3-metyi-1,3, 5pentanetriol causes the above mentioned drawbacks which were faced in the industrial practicing with alkali permanganate, to be done away with giving place also to other positive results; more detailedly the 65 advantages found with the use of nitric acid are the following:

GB 2 166 735 A 1. The absence of inorganic substances in the reaction product first of a I I makes the process readily practiceable in the industrial plants and permit meglutol to be obtained with high purity through crystallization from alkyl acetate, whereby also the use of acetonitrile is avoided which, owing to its toxicity and dangerousness, involves particular expedients to be fulfilled.

2. The yields of meglutol, according to the present process, are higherthan 60% with respect to the teoretical yield, in comparison with the 40% which can be obtained with permanganate: such a result in combination with the different price of the two oxidizing agents, causes the price of the meglutol obtained with the present process (as calculated from the raw materials only) to be sensibly reduced, it being equal to 50% of that prepared with permanganate.

3. By the process with nitric acid the volumes of reaction solvents are caused to be reduced from 4 litres/kg 10 of obtained meglutol to 8 litreslkg, and the filtration of relevant amounts of manganese dioxide (3,8kglkg meglutol) is eliminated, this operation requiring, as it is known, not negligible times, whereby also a reduction of the labour costs involved in the final product is obtained.

The process according to the invention consists in slowly adding 3-methyl1,3,5-pentanetriol to an excess of nitric acid having a density of between 1.20 and 1.50, at a rate such that, possibly with simultaneous cooling, the temperature of the reaction mixture is maintained below WC, the reaction being thereafter brough to completion within 2-6 hours at temperature of between 20-800C. Differently from the results referred to in the chemical literature as regards the oxidation reactions carried out nitric acid, in the present case if nitric acid would be used having a density lower than 1.20, meglutol would be still formed but in very yield low and accompanied by several byproducts, whereas the optimum results have been obtained with 20 nitric acid having a density higherthan 1.20, preferably of 1.35, leaving the reaction to proceed at about 300C for 2-3 hours and than carrying out a final heating for about half an hour at a temperature of between 40 and 600C.

The reaction solution is thereafter distilled under vacuum at a temperature lower than WC, part of the unreacted nitric acid being recovered, and a residue is obtained in form of a pale yellow oil which is dissolved, without difficulty, in hot butyl acetate and gives by cooling 3-hydroxy-3-methyi-glutaric acid having a title of 98% and with a yield of about 75%.

This product can be furthermore crystallized from alkyl acetates, dialkylketones or alcohols, giving place.

with a yield higher than 80%, a product having a title of about 99.5%.

The invention is more detailediy illustrated in the following example.

2 Example

In a 100OmI flask 880 g (10mol) of concentrated nitric acid (71.6%; D= 1. 42) are charged, by controlling that its temperature is not lower than 250C, and under stirring a smal I portion of 3-methyl-1,3,5-pentanetriol is added, than awaiting the development of nitrogen tetroxide and the temperature raising, these phenomena indicating that the reaction has been started; then, by externally cooling with icy water, the remaining 3-m ethyl - 1,3,5-penta netrio 1 is added, fora total amount of 142 g, at a rate such that the reaction temperature is maintained in the range of 25-WC, over about 2 hours.

Then the reaction is left to proceed to completion, the brown solution being maintained for further two hours at 25-350C and for half an hour at 50-55'C.

The final pale yellow solution is evaporated under vacuum at a temperature lower than WC, giving 210 grams of a yellowish oil, which is dissolved in the same flask in 600 mi of butyl acetate, the resulting solution is added with carbon, hot filtered and distilled undervacuum at a temperature less than WC, until 100 mi of distillate are collected: the remaining solution is cooled and there is immediately formed a colourless crystalline precipitate which is filtered at the temperature of 1WC and dried in an oven under vacuum giving 45 114'g of 3-hydroxy-3-methyl-glutaric acid having a title of 98%. The yield is about 75%. Afurther crystallization from butyl acetate gives 97g (yield 85%) of 3-hydroxy-3- methyl-glutaric acid with a title higher than 99.5%.

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Claims (7)

1. Process for the preparation of 3-hydroxy-3-methyi-glutaric acid having the formula:

OH 1 55 HOuu-Uti2-u-CH2-COOH 1 UM3 consisting in the oxidation with nitric acid of 3-m ethyl- 1,3,5-penta netrio 1.

2. A process according to claim 1, wherein the oxidation is carried out by adding 3-methyl-1,3,5pentanetriol to nitric acid, at a rate and under conditions such that the trio[ is converted to 3-hydroxy-3methyl-glutaric acid.

3. A process according to claim 2, wherein the temperature of the nitric acid at the time of the addition of 65 the trioi must be higherthan 15 'C.

3 GB 2 166 735 A 3

4. A process according to claim 3, wherein the reaction temperatures are of between 15T and 80T.

5. A process according to claims 2,3,4, wherein the nitric acid to be used has a starting density higher than 1.20.

6. A process according to claim 5, wherein the density of nitric acid is of between 1.35 and 1.45.

7. A process according to claim 6 wherein the molar ratio of nitric acid with respect to triol are of between 5 3:1 and 12A.

Printed in the UK for HMSO, D8818935, 3,86, 7102. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.